US2025313569A1PendingUtilityA1
Pharmaceutical Compounds And Compositions As Modulators Of MAS-Related G-Protein Receptor X2
Est. expiryApr 9, 2044(~17.7 yrs left)· nominal 20-yr term from priority
Inventors:Xuri GaoScott A. MitchellYat Sun OrXiben LiKevin McgrathSamuel BartlettWei LiAdam Szymaniak
C07D 401/04C07D 409/12C07D 211/56A61K 31/4709C07D 405/12C07D 491/107A61K 31/416C07D 409/14C07D 401/12A61K 31/497A61K 31/4545A61K 31/4725C07D 417/14C07D 413/14C07D 471/04A61K 31/4535C07D 405/14A61K 31/454C07D 401/14
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Claims
Abstract
The invention provides compounds of formulae (I), or pharmaceutically acceptable salts and pharmaceutical compositions thereof,which are useful as modulators of the G-coupled protein receptor MRGPRX2, as well as methods for using such compounds to treat or ameliorate certain diseases or conditions. In some embodiments, the invention provides methods for using such compounds to treat atopic dermatitis, inflammatory disorders, autoimmune disorders, itch-associated conditions, pseudo-allergic reactions, pain-associated conditions and cancer-associated conditions.
Claims
exact text as granted — not AI-modified1 . A compound of Formula (I) or pharmaceutically acceptable salt thereof:
wherein:
Z 1 is selected from the group consisting of optionally substituted aryl, optionally substituted heteroaryl, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 1 -C 8 alkoxy, optionally substituted —C 3 -C 12 cycloalkyl, and optionally substituted 3- to 12-membered heterocycloalkyl;
R 1 is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 6 alkyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, —C(O)R 11 , —C(O)OR 11 , —C(O)N(R 12 )(R 13 ) and —S(O) 2 R 11 ;
R 11 is selected from the group consisting of: optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroaryl;
R 12 and R 13 are each independently selected from the group consisting of: hydrogen, optionally substituted —C 1 -C 8 alkyl, optionally substituted —C 2 -C 8 alkenyl, optionally substituted —C 3 -C 8 cycloalkyl, optionally substituted 3- to 8-membered heterocycloalkyl, optionally substituted aryl, optionally substituted arylalkyl, optionally substituted heteroarylalkyl, and optionally substituted heteroaryl; alternatively, R 12 and R 13 are taken together with the nitrogen atom to which they are attached to form an optionally substituted 3-8 membered heterocyclic containing 0, 1, 2, or 3 double bonds;
alternatively, R 1 and Z 1 are taken together with the nitrogen atom to which they are attached to form an optionally substituted heterocyclic or an optionally substituted heteroaryl;
R 2 is selected from the group consisting of hydrogen, optionally substituted —C 1 -C 6 alkyl, and optionally substituted —C 3 -C 8 cycloalkyl;
p is 0 or 1;
L is-C(O)—, —S(O) 2 —, or absent;
Z 2 is selected from the group consisting of:
1) Optionally substituted aryl;
2) Optionally substituted heteroaryl;
3) Optionally substituted —C 3 -C 12 cycloalkyl;
4) Optionally substituted —C 3 -C 12 cycloalkenyl;
5) Optionally substituted 3- to 12-membered heterocycloalkyl;
6) Optionally substituted —C 1 -C 8 alkyl;
7) Optionally substituted arylalkyl;
8) Optionally substituted heteroarylalkyl;
9) —N(R 12 )(R 13 ); and
10) —OR 11 ;
m is 1 or 2;
n is 1 or 2; and
X is —NR 3 —, —O—, —S—, —S(O)—, or —S(O) 2 —;
R 3 is selected from the group consisting of:
1) Hydrogen;
2) Optionally substituted —C 1 -C 8 alkyl;
3) Optionally substituted —C 3 -C 8 cycloalkyl;
4) Optionally substituted 3- to 8-membered heterocycloalkyl;
5) Optionally substituted aryl;
6) Optionally substituted heteroaryl;
7) Optionally substituted arylalkyl;
8) Optionally substituted heteroarylalkyl;
9) C(O)F
10) —C(O)R 11 ;
11) —C(O)OR 11 ;
12) —C(O)N(R 12 )(R 13 ); and
13) —S(O) 2 R 11 .
2 . The compound of claim 1 represented by Formula (II):
wherein R 1 , R 2 , Z 1 , Z 2 , X, L, m and n are as defined in claim 1 .
3 . The compound of claim 1 represented by one of Formulae (XI-1)˜(XI-9):
wherein R 1 , R 2 , R 3 , Z 1 , Z 2 , and L are as defined in claim 1 .
4 . The compound of claim 1 represented by one of Formulae (XII-1)˜(XII-9):
wherein Z 1a is optionally substituted —C 3 -C 12 cycloalkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; Z 2a is optionally substituted —C 3 -C 12 cycloalkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl, or optionally substituted heteroaryl; and R 1 , R 2 , and R 3 are as defined in claim 1 .
5 . The compound of claim 1 represented by one of Formulae (XV-1)˜(XV-3):
wherein
q is 0, 1, 2, 3, or 4; r is 0, 1 or 2;
each R 21 and R 23 is independently selected from the group consisting of:
1) halogen;
2) —CN;
3) —OH;
4) —OR 11 ;
5) —NR 12 R 13 ;
6) Optionally substituted —C 1 -C 8 alkyl;
7) Optionally substituted —C 1 -C 8 haloalkyl;
8) Optionally substituted —C 3 -C 8 cycloalkyl;
9) Optionally substituted 3- to 8-membered heterocycloalkyl;
10) Optionally substituted aryl; and
11) Optionally substituted heteroaryl;
R 3a is selected from the group consisting of:
1) —C(O)R 11 ;
2) —C(O) 2 R 11 ;
3) —SO 2 R 11 ; and
4) Optionally substituted —C 1 -C 8 alkyl;
Z 2a is optionally substituted —C 3 -C 12 cycloalkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and R 11 , R 12 , and R 13 are as defined in claim 1 .
6 . The compound of claim 1 represented by one of Formulae (XV-1a)˜(XV-3a):
wherein
q is 0, 1, 2, 3, or 4; r is 0, 1 or 2;
each R 21 and R 23 is independently selected from the group consisting of:
1) halogen;
2) —CN;
3) —OH;
4) —OR 11 ;
5) —NR 12 R 13 ;
6) Optionally substituted —C 1 -C 8 alkyl;
7) Optionally substituted —C 1 -C 8 haloalkyl;
8) Optionally substituted —C 3 -C 8 cycloalkyl;
9) Optionally substituted 3- to 8-membered heterocycloalkyl;
10) Optionally substituted aryl; and
11) Optionally substituted heteroaryl;
R 3a is selected from the group consisting of:
1) Hydrogen;
2) —C(O)R 11 ;
3) —C(O) 2 R 11 ;
4) —SO 2 R 11 ;
5) Optionally substituted —C 1 -C 8 alkyl;
6) Optionally substituted 3- to 8-membered heterocycloalkyl;
7) Optionally substituted aryl; and
8) Optionally substituted heteroaryl;
Z 2a is optionally substituted —C 3 -C 12 cycloalkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and R 11 , R 12 , and R 13 are as defined in claim 1 .
7 . The compound of claim 1 represented by one of Formulae (XV-4)˜(XV-6):
wherein
v is 0 or 1; t is 0 or 1;
each R 21 and R 23 is independently selected from the group consisting of:
1) halogen;
2) —CN;
3) —OH;
4) —OR 11 ;
5) —NR 12 R 13 ;
6) Optionally substituted —C 1 -C 8 alkyl;
7) Optionally substituted —C 1 -C 8 haloalkyl;
8) Optionally substituted —C 3 -C 8 cycloalkyl;
9) Optionally substituted 3- to 8-membered heterocycloalkyl;
10) Optionally substituted aryl; and
11) Optionally substituted heteroaryl;
R 3a is selected from the group consisting of:
1) Hydrogen;
2) —C(O)R 11 ;
3) —C(O) 2 R 11 ;
4) —SO 2 R 11 ;
5) Optionally substituted —C 1 -C 8 alkyl;
6) Optionally substituted 3- to 8-membered heterocycloalkyl;
7) Optionally substituted aryl; and
8) Optionally substituted heteroaryl;
Z 2a is optionally substituted —C 3 -C 12 cycloalkyl, optionally substituted 3- to 12-membered heterocycloalkyl, optionally substituted aryl or optionally substituted heteroaryl; and R 11 , R 12 , and R 13 are as defined in claim 1 .
8 . The compound of claim 1 represented by one of Formulae (XVII-1a)˜(XVII—
wherein:
v is 0 or 1; t is 0 or 1; q is 0, 1, 2, 3 or 4; r is 0, 1 or 2;
each R 21 and R 23 is independently selected from the group consisting of:
1) halogen;
2) —CN;
3) —OH;
4) —OR 11 ;
5) —NR 12 R 13 ;
6) Optionally substituted —C 1 -C 8 alkyl;
7) Optionally substituted —C 1 -C 8 haloalkyl;
8) Optionally substituted —C 3 -C 8 cycloalkyl;
9) Optionally substituted 3- to 8-membered heterocycloalkyl;
10) Optionally substituted aryl; and
11) Optionally substituted heteroaryl;
each R 22 is independently selected from the group consisting of:
1) halogen;
2) —CN;
3) —OH;
4) —OR 11 ;
5) —NR 12 R 13 ;
6) Optionally substituted —C 1 -C 8 alkyl;
7) Optionally substituted —C 1 -C 8 haloalkyl;
8) Optionally substituted —C 3 -C 8 cycloalkyl;
9) Optionally substituted 3- to 8-membered heterocycloalkyl;
10) Optionally substituted aryl; and
11) Optionally substituted heteroaryl;
each R 24 is independently selected from the group consisting of:
1) halogen;
2) —NR 12 R 13 ;
3) Optionally substituted —C 1 -C 8 alkyl;
4) Optionally substituted —C 1 -C 8 haloalkyl;
5) Optionally substituted —C 3 -C 8 cycloalkyl;
6) Optionally substituted 3- to 8-membered heterocycloalkyl;
7) Optionally substituted aryl; and
8) Optionally substituted heteroaryl;
each R 25 is independently selected from the group consisting of:
1) hydrogen;
2) Optionally substituted —C 1 -C 8 alkyl;
3) Optionally substituted —C 1 -C 8 haloalkyl;
4) Optionally substituted —C 3 -C 8 cycloalkyl;
5) Optionally substituted 3- to 8-membered heterocycloalkyl;
6) Optionally substituted aryl; and
7) Optionally substituted heteroaryl;
and R 3a is selected from the group consisting of:
1) Hydrogen;
2) —C(O)R 11 ;
3) —C(O) 2 R 11 ;
4) —SO 2 R 11 ;
5) Optionally substituted —C 1 -C 8 alkyl;
6) Optionally substituted 3- to 8-membered heterocycloalkyl;
7) Optionally substituted aryl; and
8) Optionally substituted heteroaryl.
9 . A compound selected from the compounds set forth below, or a pharmaceutically acceptable salt thereof:
Compound
Structure
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10 . A pharmaceutical composition comprising the compound of claim 1 and a pharmaceutically acceptable carrier.
11 . A method for treating a disease, disorder, or condition where modulation of a MRGPR is implicated, wherein the method comprises administering to a system or subject in need of such treatment an effective amount of the compound of claim 1 , wherein the MRGPR is MRGPR X2.
12 . The method of claim 11 , wherein the disease, disorder or condition is a pseudo-allergic reaction, an itch associated condition, a pain associated condition, an inflammatory or autoimmune disorder.
13 . The method of claim 12 , wherein the itch associated condition is chronic itch; contact dermatitis; Allergic blepharitis; Anemia; Atopic dermatitis; Bullous pemphigoid; Candidiasis; Chicken pox; end-stage renal failure; hemodialysis; Chronic urticaria; Contact dermatitis, Atopic Dermatitis; Dermatitis herpetiformis; Diabetes; Drug allergy, Dry skin; Dyshidrotic dermatitis; Ectopic eczema; Eosinophilic fasciitis; Epidermolysis bullosa; Erythrasma; Food allergy; Folliculitis; Fungal skin infection; Hemorrhoids; Herpes; HIV infection; Hodgkin's disease; Hyperthyroidism; Iodinated contrast dye allergy; Iron deficiency anemia; Kidney disease; Leukemia, porphyrias; Lymphoma; Malignancy; Mastocystosis; Multiple myeloma; Neurodermatitis; Onchocerciasis; Paget's disease; Pediculosis; Polycythemia rubra vera; Prurigo nodularis; Lichen Planus; Lichen Sclerosis; Pruritus ani; Pseudorabies; Psoriasis; Rectal prolapse; Sarcoidosis granulomas; Scabies; Schistosomiasis; Scleroderma, Severe stress, Stasia dermatitis; Swimmer's itch; Thyroid disease; Tinea cruris; Rosacea; Cutaneous amyloidosis; Scleroderma; Acne; wound healing; burn healing; ocular itch; or Urticaria.
14 . The method of claim 12 , wherein the itch associated condition is urticaria, pruritus, atopic dermatitis, dry skin, psoriasis, contact dermatitis, or eczema.
15 . The method of claim 12 , wherein the pain associated condition is Acute Pain, Advanced Prostate Cancer, AIDS-Related Pain, Ankylosing Spondylitis, Arachnoiditis, Arthritis, Arthrofibrosis, Ataxic Cerebral Palsy, Autoimmune Atrophic Gastritis, Avascular Necrosis, Back Pain, Behcet's Disease (Syndrome), Burning Mouth Syndrome, Bursitis, Cancer Pain, Carpal Tunnel, Cauda Equina Syndrome, Central Pain Syndrome, Cerebral Palsy, Cervical Stenosis, Charcot-Marie-Tooth (CMT) Disease, Chronic Fatigue Syndrome (CFS), Chronic Functional Abdominal Pain (CFAP), Chronic Pain, Chronic Pancreatitis, Chronic Pelvic Pain Syndrome, Collapsed Lung (Pneumothorax), Complex Regional Pain Syndrome (RSD), Corneal Neuropathic Pain, Crohn's Disease, Degenerative Disc Disease, Dental Pain, Dercum's Disease, Dermatomyositis, Diabetic Peripheral Neuropathy (DPN), Dystonia, Ehlers-Danlos Syndrome (EDS), Endometriosis, Eosinophilia-Myalgia Syndrome (EMS), Erythromelalgia, Fibromyalgia, Gout, Headaches, Herniated disc, Hydrocephalus, Intercostal neuralgia, Interstitial Cystitis, Irritable Bowel syndrome (IBS), Juvenile Dermatositis (Dermatomyositis), Knee Injury, Leg Pain, Loin Pain-Haematuria Syndrome, Lupus, Lyme Disease, Medullary Sponge Kidney (MSK), Meralgia Paresthetica, Mesothelioma, Migraine, Musculoskeletal pain, Myofascial Pain, Myositis, Neck Pain, Neuropathic Pain, Occipital Neuralgia, Osteoarthritis, Paget's Disease, Parsonage Turner Syndrome, Pelvic Pain, Periodontitis Pain, Peripheral Neuropathy, Phantom Limb Pain, Pinched Nerve, Polycystic Kidney Disease, Polymyalgia Rhuematica, Polymyositis, Porphyria, Post Herniorrhaphy Pain Syndrome, Post Mastectomy, Postoperative Pain, Pain Syndrome, Post Stroke Pain, Post Thorocotomy Pain Syndrome, Postherpetic Neuralgia (Shingles), Post-Polio Syndrome, Primary Lateral Sclerosis, Psoriatic Arthritis, Pudendal Neuralgia, Radiculopathy, Raynaud's Disease, Rheumatoid Arthritis (RA), Sacroiliac Joint Dysfunction, sarcoidosis, Scheuermann's Kyphosis Disease, Sciatica, Scoliosis, Shingles (Herpes Zoster), Sjogren's Syndrome, Spasmodic Torticollis, Sphincter of Oddi Dysfunction, Spinal Cerebellum Ataxia (SCA Ataxia), Spinal Cord Injury, Spinal Stenosis, Syringomyelia, Tarlov Cysts, Transverse Myelitis, Trigeminal Neuralgia, Neuropathic Pain, Ulcerative Colitis, Vascular Pain or Vulvodynia.
16 . The method of claim 12 , wherein the inflammatory or autoimmune disorder is chronic inflammation, mast cell activation syndrome, Multiple Sclerosis, Steven Johnson's Syndrome, Toxic Epidermal Necrolysis, appendicitis, bursitis, cutaneous lupus, colitis, cystitis, dermatitis, phlebitis, reflex sympathetic dystrophy/complex regional pain syndrome (rsd/crps), rhinitis, tendonitis, tonsillitis, acne vulgaris, sinusitis, rosacea, psoriasis, graft-versus-host disease, reactive airway disorder, asthma, airway infection, autoinflammatory disease, celiac disease, chronic prostatitis, diverticulitis, glomerulonephritis, hidradenitis suppurativa, hypersensitivities, intestinal disorder, epithelial intestinal disorder, inflammatory bowel disease, irritable bowel syndrome, Crohn's Disease, ulcerative colitis, lupus erythematous, interstitial cystitis, otitis, pelvic inflammatory disease, endometrial pain, reperfusion injury, rheumatic fever, rheumatoid arthritis, sarcoidosis, transplant rejection, psoriasis, lung inflammation, chronic obstructive pulmonary disease, cardiovascular disease, or vasculitis.
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